Composite dosage forms

ABSTRACT

A composite dosage form comprises at least one active ingredient, a first portion comprising a first molded material, and a second portion comprising a second material which is compositionally different from the first material. The first and second portions are joined at an interface, and a surface of the first portion at the interface resides substantially conformally upon a surface of the second portion of the interface. Either the first portion, the second portion, or a combination thereof may contain at least one active ingredient. The first portion, second portion or both may also each comprise an insert which may contain at least one active ingredient. The dosage form may also comprise a third portion which is located between the first and second portions.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to composite dosage forms such as pharmaceuticalcompositions. More particularly, this invention relates to compositedosage forms comprising at least one active ingredient and having afirst portion comprising a first molded material and a second portioncomprising a second material, in which the second material iscompositionally different than the first material, surfaces of the firstand second portions are joined at an interface, and the first portionsurface at the interface resides substantially conformally upon thesecond portion surface at the interface.

2. Background Information

Dosage forms having two or more distinct portions are useful in thepharmaceutical arts for overcoming a number of commonly encounteredchallenges, including the separation of incompatible active ingredients,achieving acceptable content uniformity of a low-dose/high potencyactive ingredient, delivering one or more active ingredients in apulsatile manner, and providing unique aesthetic characteristics fordosage form identification. Known methods for achieving a multi-portionpharmaceutical dosage form include particle coating, multi-layertablets, compression-coating, and spray coating techniques. It is alsoknown for example in the household products industry to assemble solidforms from two or more different parts for the purpose of separatingactive ingredients, or delivering different active ingredients atdifferent times.

Dosage forms comprising coated particles are described for example inU.S. Pat. No. 5,593,696, which describes oral dosage forms for treatingof gastric disorders. The dosage forms contain, as active ingredients,famotidine and sucralfate. In the dosage form, the famotidine is presentin the composition in particulate (granulate) form, and the particulatefamotidine is provided with a protective barrier layer which preventsinteraction between the famotidine and the sucralfate in thecomposition. The barrier layer is preferably a polymeric coat whichdissolves partially in vivo in the stomach environs to release thecoated famotidine. U.S. Pat. No. 5,980,944 describes a solid oral dosageform for the treatment of gastrointestinal disorders comprising atherapeutically effective amount of a pharmaceutical suitable for thetreatment of gastric disorders selected from the group consisting ofgranules of diphenoxylate, loperamide, loperamide-N-oxide,pharmaceutically acceptable salts thereof and combinations thereof, anda therapeutically effective amount of simethicone wherein thepharmaceutical and simethicone are separated by a barrier coat on thegranules which is substantially impermeable to simethicone.

Multi-layer tablets are described, for example, in U.S. Pat. No.5,200,193, which describes multi-layered pharmaceutical active tabletscomprising an immediate release layer and a homogeneous compressedsustained release layer comprising an erosion promoter, which uponadministration results in a long-lasting, slow and relatively regularincremental release of the pharmaceutical active ingredient. U.S. Pat.No. 6,372,252 describes a pharmaceutical sustained release formulationcapable of providing therapeutically effective bioavailability ofguaifenesin for at least twelve hours after dosing in a human subject.The modified release guaifenesin bi-layer tablet disclosed has a firstportion comprising an immediate release formulation of guaifenesin and asecond portion comprising a sustained release formulation ofguaifenesin. U.S. Pat. No. 4,999,226 discloses a multi-layered tabletcontaining an ibuprofen layer, a piperidino-alkanol antihistamine layer,and a layer or layers containing conventional pharmaceutical excipientswhich is interspersed between the ibuprofen and piperidino-alkanol layerand serves to physically separate them. This multi-layered tablet solvesthe problems associated with the physical and chemical incompatibilitiesbetween ibuprofen and the piperidinoalkanol antihistamines. U.S. Pat.No. 4,198,390 describes a tablet containing at least two separate anddiscrete volume portions, one of which contains simethicone and theother of which contains antacid. A barrier separates the two volumeportions to maintain the simethicone out of contact with the antacid andto prevent migration of the simethicone from its volume portion of thetablet into the volume portion containing the antacid, and vice versa.U.S. Pat. No. 5,133,892 describes a multilayer detergent tabletcontaining an outer layer, a barrier layer and an inner layer. Thetablet sequentially releases ingredients contained in the outer layerand ingredients contained in the inner layer. The time interval betweenthe release of the outer layer ingredients and the release of the innerlayer ingredients is controlled by the particular choice of aningredient for the barrier layer and the relative thicknesses of theinner layer, the barrier layer and the outer layer. The tablet is ableto separate in time the dissolution of incompatible ingredients such asan enzyme and a chlorine bleach. The tablet also provides sequentialrelease of a dishwashing composition and a rinse aid composition suchthat cleaning is accomplished prior to the release of the rinse aid.

Compression-coated tablets are useful for separation of incompatibleactive ingredients, and for pulsatile release of one or more activeingredients. Compressed coatings may have shapes which are substantiallyindependent of the shape of the core, as disclosed for example in WO00/18447. Commercially available compression coating machines areavailable for example from Korsch America Inc., a subsidiary of KorschAG, and described in WO 89/11968. Modified release dosage forms preparedvia compression are exemplified in U.S. Pat. Nos. 5,738,874 and6,294,200, and WO 99/51209. It is possible, via compression-coating, toproduce a 2-portion shell, which may function as a barrier, or releasedelaying coating; however compression-coated systems are limited by theshell thickness and shell composition as well as processing costs.Gunsel et al., “Compression-Coated and Layer Tablets” in PharmaceuticalDosage Forms—Tablets, edited by H. A. Lieberman, L. Lachman, J. B.Schwartz (2nd ed., rev. and expanded Marcel Dekker, Inc.) pp. 247-284,for example, discloses the thickness of compression coated shells istypically between 800 and 1200 microns. Additionally these authors notethat “the advent of film coating dissipated much of the advantage of drycoating since larger quantities of tablets can be coated in a short timewith film-formers dissolved in organic or aqueous solvents.” Typically,compressed coatings must contain a substantial amount of a compressiblematerial. The compressed shell of WO 00/18447, for example, employsmicrocrystalline cellulose at a level of about 30%.

One method for addressing the challenge of low-dose/high potency activesis described for example in U.S. Pat. No. 4,322,449 and U.S. RE 31764,which disclose a method for the preparation of pharmaceuticals whichcomprises using a piezoelectric dosing system to dot liquid, dissolvedor suspended active substance onto a pharmaceutical carrier. Thedisclosed method enables precise dosing of active pharmaceuticalingredients onto pharmaceutical carriers. The dotting is effected by,for example, use of tubular or plate-shaped piezoelectric dosingsystems. However, the liquid, dissolved or suspended active substancecan also be divided into discrete droplets of specific volume afterapplication of a high pressure during passage through a narrow nozzle,whereby the individual droplets are successively charged electricallyand are intermittently deflected electrostatically towards thepharmaceutical carriers.

The incorporation of molded portions into delivery systems has been usedin the household products industry to achieve an additional degree ofversatility. Assembled forms comprising a mixture of compressed andmolded portions are known for example for delivery of detergents. WO01/49815 describes a composition for use in a dishwasher characterizedby a base composition in the form of a tablet which becomes activesubstantially during the main wash cycle, and at least one separate zonein or on the tablet is provided with a substance that becomes activesubstantially during the rinse cycle of the dishwasher. One example ofsuch assembled forms comprises a compressed tablet portion having ahemispherical indentation in a major face, and a molded sphericalportion fit into and adhered to the indentation in the compressedportion. One limitation of such assemblies is the propensity for the twoportions to become detached due to inadequate adherance and minimalsurface area of contact between them. In such assemblies, the moldedportion may be smaller than the indentation in the compressed portion,e.g. the diameter of the molded portion is at least about 20 micronsless that the diameter of the opening in the compressed portion.Alternatively, similar forms may be assembled by press-fitting. In theseforms the dimensions of the molded portion and the opening in thecompressed portion may be similar. Such assemblies are additionallylimited in the types of geometries that are possible at the interface.In press-fit assemblies, the width of the molded portion at the deepestpart of the interface may not be substantially larger than the width ofthe opening through which it must be fit. In other words the draft anglebetween the outer and inner surfaces of the compressed portion may notbe negative. Moreover, the interface or area of contact between the twoportions may not form an interlock.

Another significant opportunity in designing pharmaceutical dosage formsis that of product identification and differentiation. It is useful,both from a consumer safety perspective, and a commercial perspective,to have a dosage form with a unique appearance that is readilyrecognizable and identifiable.

Current techniques for providing unique dosage form identificationinclude the use of intagliations. Intagliations are impressed markstypically achieved by engraving or impressing of a graphicalrepresentation, for example a figure, mark, character, symbol such as aletter, a name, a logo, a pictoral representation, and the like, or anycombination thereof, in a tablet or other solid dosage form, preferablyby a punching procedure. U.S. Pat. No. 5,827,535, for example, describessoft gelatin capsules having an external surface having defined thereonan impressed graphical representation. U.S. Pat. No. 5,405,642 disclosesa method of highlighting intagliations in white or colored coatedtablets by spraying onto said tablets a suspension comprising a fillingmaterial having a different color, a waxy material and a solvent, andremoving the solvent and the excess of filling material and waxymaterial. The suspension of U.S. Pat. No. 5,405,642 comprises a waxymaterial and a filling material in a critical weight ratio from about1:3 to about 1:12. Too little waxy material will lead to insufficientbonding of the filling material; too much waxy material the fillingmaterial will bond too strongly to the tablet surface and consequentlywill be difficult to remove afterwards. Suitable solvents for thesuspension of U.S. Pat. No. 5,405,642 are those solvents wherein thefilling material and, if present, the dye, do not dissolve. For example,non-dyed starches and celluloses may be suspended in alcohols, e.g.ethanol, isopropanol and the like, halogenated hydrocarbons, e.g.dichloromethane, trichloromethane and the like. EP 060,023 discloses amethod of emphasizing intagliations in colored (i.e. not white) solidarticles, in particular tablets, by coating the tablet surface andfilling up the intagliations with a coating film comprising an opticallyanisotropic substance. An optical contrast between the tablet surfaceand the intagliations is obtained, presumably due to the differentorientation of the optically anisotropic substance on the tablet surfaceand in the intagliations. The technique is limited to colored articlesand only allows the use of optically anisotropic filling materials. Theoptical effect merely being based on a different contrast is notparticularly clear.

EP 088,556 relates to a method of highlighting intagliations in white orcolored tablets by contacting said tablets with a dry, powdery materialhaving a different color than the tablet surface and then removing theexcess powdery material not deposited in the intagliations. The powderymaterial is thought to adhere better to the intagliations of coatedtablets than to those of uncoated tablets. Adherence can further beincreased by using a mixture of a wax and a powdery material as thedeposition material and heating the filled tablets to 40° C.-90° C. tomelt the wax. Finally, an outer coating may be applied to the filledtablets. However, the method disclosed in EP 088,556 has severalproblems. First, it has been found that the adhesion of the powderymaterial to the intagliations is not satisfactory as the material showsa tendency to loosen and fall out. This problem arises particularly whenan outer coating film is applied to the filled tablet and the loosenedmaterial becomes fixed in the outer coating film, thus yielding speckledtablets. Addition of a wax to the powdery material to improve adhesion,on the other hand, adversely affects the distribution of the powderymaterial in that more of it sticks to the surface of the tablet and isdifficult to remove. Several other drawbacks are associated with the useof a wax in the dry powdery material. In particular the necessity toheat the tablets filled with a wax and a powdery material to melt thewax poses a barely acceptable risk since many medicines are thermolabileand might deteriorate significantly in the process. Further, it isdifficult to evenly dye a dry mixture of a wax and a powdery material,which in turn puts a limitation on the effectively possible colorcombinations.

U.S. Pat. No. 4,139,589 describes a process for the manufacture of aninlaid tablet, comprising the steps of incorporating into a plasticchewing gum mass a sustained-release active ingredient; incorporatinginto a non-plastic tablet mass a substantially immediate-releasepharmaceutically active ingredient; and respectively converting thechewing gum mass and the tablet mass into the core and the outer layerof the inlaid tablet. A preferred embodiment includes converting thetablet mass into a recessed preformed element, converting the chewinggum mass into the core, inserting the core into the recess of thepreformed element, introducing the preformed element and the core into atablet mold, and subjecting the preformed element and the core in themold to pressure.

All of the methods described above for producing a dosage form havingone or more separate portions are relatively costly, complex, andtime-intensive. Additionally, known methods for producing filled-inintagliations are limited in terms of suitable materials and theobtainable surface configurations and appearance of the resultant dosageform. Besides the above-mentioned limitations on the fill materialitself, the tablet subcoating must be non-adhesive enough for thefill-in material to rub off upon tumbling in a hot coating pan. Thesemethods cannot produce filled-in intagliations having the fill materialraised above the tablet surface, or even perfectly flush with the tabletsurface. The prior art product can only have a fill-in material surfacethat is slightly depressed, abraided, or concave with respect to thetablet surface.

Another significant challenge in the pharmaceutical industry is theopportunity to minimize manufacturing and packaging costs throughstandardization. Many drugs are available in several different strengthtablets for convenience of dosing different patients with varying needs.Typically, higher strength tablets have greater weight and larger sizethan tablets having lower amounts of active ingredient. Handling andpackaging costs could be reduced by having a dosage form design with theversatility to accommodate multiple different dosage amounts ofmedication in the same size tablet, yet be readily identifiable topatients and healthcare professionals in terms of identity and strength.

All of the prior art methods for forming a shell on a core share thecommon limitation of having the shape of the shell depend upon andgenerally conform to the shape of the core. Other limitations shared byconventional encapsulation and enrobing processes include high cost andcomplexity, limitations on the thickness of the coating or shell, andthe creation of raised seams between capsule halves and/or coatings.

In addition, the separation of incompatible ingredients inpharmaceutical dosage forms presents a significant challenge to theformulator. This challenge has primarily been addressed in the artthrough the use of relatively costly and time-intensive methods ofcoated particles, multiple layer compressed tablets, or compressioncoating.

Another significant challenge in the formulation of pharmaceuticaldosage forms is that of providing multiple release profiles for multipleactive ingredients. This challenge has primarily been addressed in theart through the use of coated particles, or sprayed or compressed tabletcoatings, all of which add cost and complexity to the manufacturingprocess.

The incorporation of molded portions into delivery systems, has beenused in the household products industry to achieve an additional degreeof versatility. Assembled forms comprising a mixture of compressed andmolded portions are known, for example, for delivery of detergents. WO01/49815 describes a composition for use in a dishwasher characterizedby a base composition in the form of a tablet which becomes activesubstantially during the main wash cycle, and at least one separate zonein or on the tablet is provided with a substance that becomes activesubstantially during the rinse cycle of the dishwasher. One example ofsuch assembled forms comprises a compressed tablet portion having ahemispherical indentation in a major face, and a molded sphericalportion fit into and adhered to the indentation in the compressedportion. However, a limitation of such assemblies is the propensity forthe two portions to become detached due to inadequate adherance andminimal surface area of contact therebetween. In such assemblies, themolded portion may be smaller than the indentation in the compressedportion, e.g. the diameter of the molded portion is at least about 20microns less that the diameter of the opening in the compressed portion.Alternatively, similar forms may be assembled by press-fitting. In theseforms the dimensions of the molded portion and the opening in thecompressed portion may be similar. Such assemblies are additionallylimited in the types of geometries that are possible at the interface.In press-fit assemblies, the width of the molded portion at the deepestpart of the interface may not be substantially larger than the width ofthe opening through which it must be fit. In other words, the “draftangle” between the outer and inner surfaces of the compressed portionmay not be negative. Moreover, the interface or area of contact betweenthe two portions may not form an interlock.

Accordingly, it is one object of this invention to provide a dosage formcomprising at least one active ingredient and a first portion comprisinga first molded material and a second portion comprising a secondmaterial, in which the second material is compositionally different thanthe first material, the first and second material are joined at aninterface, and a surface of the first portion at the interface residessubstantially conformally upon a surface of the second portion of theinterface.

It is another object of this invention to provide a dosage formcomprising at least one active ingredient, a first portion comprising afirst molded material, a second portion comprising a second materialwhich is compositionally different from the first material, and a thirdportion which is located between the first and second portions.

Dosage forms of the present invention advantageously have enhancedversatility for a number of applications, including dosage forms todeliver pharmaceuticals, nutritionals and/or confections, which mayoffer benefits of improved swallowability for an irregularly shapedsubstrate, or unique and pleasant aesthetic qualities that are valuablein the marketplace.

The dosage form of the present invention also advantageously provides acost-effective means for ensuring acceptable content uniformity, andimproved safety of handling for low-dose/high potency activeingredients. Low dose active ingredients can be homogeneously dispersedin the molded portion when it is in a flowable state. This eliminatesproblems associated with powder segregation in blends for tableting, andminimizes exposure of workers to potential inhalation of dust containingthe high potency active ingredient.

Other objects, features and advantages of this invention will beapparent to those skilled in the art from the detailed description ofthe invention provided herein.

SUMMARY OF THE INVENTION

The dosage form of this invention comprises at least one activeingredient, a first portion comprising a first molded material and asecond portion comprising a second material which is compositionallydifferent than the first material. For example, the second material maybe a compressed material such as a compressed powder. Surfaces of thefirst and second portions are joined at an interface, such that thesurface of the first portion resides substantially conformally upon thesurface of the second portion at the interface.

In one embodiment, the first portion comprises a thermoplastic material.

In another embodiment, the first molded material is substantially freeof pores having a diameter of 0.5 to 5.0 microns.

In another embodiment, the first portion comprises a foam.

In another embodiment, the first portion comprises an aerated material.

In another embodiment, the active ingredient is coated with arelease-modifying coating.

In another embodiment, the first and second portions are in substantialcontact at the interface.

In another embodiment, the interface is in the form of an abutment.

In another embodiment, the first and second portions overlap at theinterface.

In another embodiment, the first and second portions interlock at theinterface.

In another embodiment, the first and second portions dissociate uponimmersion in aqueous media.

In another embodiment, the dosage form further comprises a thirdportion, which is located between the first and second portions.

In another embodiment, the third portion comprises a chemical reactionproduct of the first and second materials.

In another embodiment, the third portion is impermeable to one or moreactive ingredients contained in the dosage form.

In another embodiment, the third portion is impermeable to water.

In another embodiment, the third portion acts as a barrier to thepassage therethrough of one or more active ingredients contained in thefirst or second portions.

In another embodiment, the third portion functions to control thepassage of one or more active ingredients contained in the first orsecond portions.

In another embodiment, the third portion comprises openings which allowthe passage of one or more active ingredients therethrough.

In another embodiment, the third portion comprises a microelectronicdevice.

In another embodiment, the first and second portions have differentcolors.

In another embodiment, the first and second portions have differentopacities.

In another embodiment, the first and second portions have differentsolubilities in acidic, alkaline, or neutral aqueous media.

In another embodiment, the first and second portions have differentdissolution rates in acidic, alkaline, or neutral aqueous media.

In another embodiment, the first and second portions have differentdisintegration times in acidic, alkaline, or neutral aqueous media.

In another embodiment, the first and second portions have differenthydrophilicities.

In another embodiment, the first and second portions have differenttopographies.

In another embodiment, the first and second portions have differentelasticities.

In another embodiment, the first and second portions have differentplasticities.

In another embodiment, the first and second portions have differenttensile strengths.

In another embodiment, the first and second portions have differentcrystallinities.

In another embodiment, the first and second portions each comprise atleast one active ingredient, and release active ingredient at differentrates.

In another embodiment, the first portion is obtained by injectionmolding.

In another embodiment, the second portion is a substrate, and the firstportion is formed directly upon the first portion.

In another embodiment, the first portion comprises at least one activeingredient.

In another embodiment, the second portion comprises at least one activeingredient.

In another embodiment, the first and the second portion each comprise atleast one active ingredient which may be the same or different.

In another embodiment, the first portion further comprises an insert.

In another embodiment, the second portion further comprises an insert.

In another embodiment, the insert is molded.

In another embodiment, the first portion is contained within the secondportion.

In another embodiment, at least one active ingredient is capable ofdissolution, and dissolution of the active ingredient meets USPspecifications for immediate release tablets containing the activeingredient.

In another embodiment, the second material is a compressed material.

In another embodiment, either the first portion, the second portion orboth comprises a microelectronic device.

In another embodiment, a shell resides upon the outer surfaces of thefirst and second portions.

In another embodiment, the surface of the first portion at the interfacehas indentations and protrusions corresponding substantially inverselyto indentations and protrusions on the surface of the second portion atthe interface.

In another embodiment, wherein the indentations and protrusions have alength, width, height or depth greater than 10 microns.

In another embodiment, the area of the interface surfaces is at least50% of the area of a major face of either the first or second portion.

In another embodiment, an entire face of the first portion is insubstantial contact with the second portion.

In another embodiment, an entire face of the second portion is insubstantial contact with the first portion.

In another embodiment, a side or face of the second portion comprises acavity, and the first portion is in contact with the entire surface ofthe cavity.

In another embodiment, at least one exterior surface of the firstportion is flush with at least one exterior surface of the secondportion.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B are top and side views of an embodiment of thisinvention.

FIGS. 2A and 2B are top and side views of another embodiment of thisinvention.

FIGS. 3A and 3B are top and side views of another embodiment of thisinvention.

FIGS. 4A and 4B are top and side views of another embodiment of thisinvention.

FIGS. 5A and 5B are top and side views of another embodiment of thisinvention.

FIGS. 6A and 6B are top and side views of another embodiment of thisinvention.

FIGS. 7A-7C are top, side and exploded views of another embodiment ofthis invention.

FIGS. 8A-8C side views of other embodiments of this invention.

FIGS. 9A and 9B are top and side views of another embodiment of thisinvention.

FIG. 10 is a side view of another embodiment of this invention.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “dosage form” applies to any solid object,semi-solid, or liquid composition, designed to contain a specificpre-determined amount (i.e. dose) of a certain ingredient, for examplean active ingredient as defined below. Suitable dosage forms may bepharmaceutical drug delivery systems, including those for oraladministration, buccal administration, rectal administration, topical,transdermal, or mucosal delivery, or subcutaneous implants, or otherimplanted drug delivery systems; or compositions for deliveringminerals, vitamins and other nutraceuticals, oral care agents,flavorants, and the like. Preferably the dosage forms of the presentinvention are considered to be solid, however they may contain liquid orsemi-solid components. In a particularly preferred embodiment, thedosage form is an orally administered system for delivering apharmaceutical active ingredient to the gastro-intestinal tract of ahuman. In another preferred embodiment, the dosage form is an orallyadministered “placebo” system containing pharmaceutically inactiveingredients, and the dosage form is designed to have the same appearanceas a particular pharmaceutically active dosage form, such as may be usedfor control purposes in clinical studies to test, for example, thesafety and efficacy of a particular pharmaceutically active ingredient.

Suitable active ingredients for use in the dosage form of this inventioninclude for example pharmaceuticals, minerals, vitamins and othernutraceuticals, oral care agents, flavorants and mixtures thereof.Suitable pharmaceuticals include analgesics, anti-inflammatory agents,antiarthritics, anesthetics, antihistamines, antitussives, antibiotics,anti-infective agents, antivirals, anticoagulants, antidepressants,antidiabetic agents, antiemetics, anti flatulents, antifungal s,antispasmodics, appetite suppressants, bronchodilators, cardiovascularagents, central nervous system agents, central nervous systemstimulants, decongestants, diuretics, expectorants, gastrointestinalagents, migraine preparations, motion sickness products, mucolytics,muscle relaxants, osteoporosis preparations, polydimethylsiloxanes,respiratory agents, sleep-aids, urinary tract agents and mixturesthereof.

Suitable oral care agents include breath fresheners, tooth whiteners,antimicrobial agents, tooth mineralizers, tooth decay inhibitors,topical anesthetics, mucoprotectants, and the like.

Suitable flavorants include menthol, peppermint, mint flavors, fruitflavors, chocolate, vanilla, bubblegum flavors, coffee flavors, liqueurflavors and combinations and the like.

Examples of suitable gastrointestinal agents include antacids such ascalcium carbonate, magnesium hydroxide, magnesium oxide, magnesiumcarbonate, aluminum hydroxide, sodium bicarbonate, dihydroxyaluminumsodium carbonate; stimulant laxatives, such as bisacodyl, cascarasagrada, danthron, senna, phenolphthalein, aloe, castor oil, ricinoleicacid, and dehydrocholic acid, and mixtures thereof; H2 receptorantagonists, such as famotadine, ranitidine, cimetadine, nizatidine;proton pump inhibitors such as omeprazole or lansoprazole;gastrointestinal cytoprotectives, such as sucraflate and misoprostol;gastrointestinal prokinetics, such as prucalopride, antibiotics for H.pylori, such as clarithromycin, amoxicillin, tetracycline, andmetronidazole; antidiarrheals, such as diphenoxylate and loperamide;glycopyrrolate; antiemetics, such as ondansetron, analgesics, such asmesalamine.

In one embodiment of the invention, the active agent may be selectedfrom bisacodyl, famotadine, ranitidine, cimetidine, prucalopride,diphenoxylate, loperamide, lactase, mesalamine, bismuth, antacids, andpharmaceutically acceptable salts, esters, isomers, and mixturesthereof.

In another embodiment, the active agent is selected from analgesics,anti-inflammatories, and antipyretics, e.g. non-steroidalanti-inflammatory drugs (NSAIDs), including propionic acid derivatives,e.g. ibuprofen, naproxen, ketoprofen and the like; acetic acidderivatives, e.g. indomethacin, diclofenac, sulindac, tolmetin, and thelike; fenamic acid derivatives, e.g. mefanamic acid, meclofenamic acid,flufenamic acid, and the like; biphenylcarbodylic acid derivatives, e.g.diflunisal, flufenisal, and the like; and oxicams, e.g. piroxicam,sudoxicam, isoxicam, meloxicam, and the like. In a particularlypreferred embodiment, the active agent is selected from propionic acidderivative NSAID, e.g. ibuprofen, naproxen, flurbiprofen, fenbufen,fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen,oxaprozin, pranoprofen, suprofen, and pharmaceutically acceptable salts,derivatives, and combinations thereof.

In another embodiment of the invention, the active agent may be selectedfrom acetaminophen, acetyl salicylic acid, ibuprofen, naproxen,ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, meloxicam,rofecoxib, celecoxib, and pharmaceutically acceptable salts, esters,isomers, and mixtures thereof.

In another embodiment of the invention, the active agent may be selectedfrom pseudoephedrine, phenylpropanolamine, chlorpheniramine,dextromethorphan, diphenhydramine, astemizole, terfenadine,fexofenadine, loratadine, desloratidine, doxilamine, norastemizole,cetirizine, mixtures thereof and pharmaceutically acceptable salts,esters, isomers, and mixtures thereof.

Examples of suitable polydimethylsiloxanes, which include, but are notlimited to dimethicone and simethicone, are those disclosed in U.S. Pat.Nos. 4,906,478, 5,275,822, and 6,103,260, the contents of each isexpressly incorporated herein by reference. As used herein, the term“simethicone” refers to the broader class of polydimethylsiloxanes,including but not limited to simethicone and dimethicone.

The active ingredient or ingredients are present in the dosage form in atherapeutically effective amount, which is an amount that produces thedesired therapeutic response upon oral administration and can be readilydetermined by one skilled in the art. In determining such amounts, theparticular active ingredient being administered, the bioavailabilitycharacteristics of the active ingredient, the dose regime, the age andweight of the patient, and other factors must be considered, as known inthe art. In one particular embodiment, the first or second portioncomprises at least about 85 weight percent of the active ingredient.

If the active ingredient has an objectionable taste, and the dosage formis intended to be chewed or disintegrated in the mouth prior toswallowing, the active ingredient may be coated with a taste maskingcoating, as known in the art. Examples of suitable taste maskingcoatings are described in U.S. Pat. No. 4,851,226, U.S. Pat. No.5,075,114, and U.S. Pat. No. 5,489,436. Commercially available tastemasked active ingredients may also be employed. For example,acetaminophen particles which are encapsulated with ethylcellulose orother polymers by a coaccervation process may be used in the presentinvention. Coaccervation-encapsulated acetaminophen may be purchasedcommercially from Eurand America, Inc. (Vandalia, Ohio) or from CircaInc., (Dayton, Ohio).

In embodiments where an active ingredient is contained within the firstor second portion of the dosage form, at least a portion of the activeingredient may be optionally coated with a release-modifying coating, asknown in the art. This advantageously provides an additional tool formodifying the release profile of the dosage form. Examples of suitablerelease modifying coatings are described, for example, U.S. Pat. Nos.4,173,626; 4,863,742; 4,980,170; 4,984,240; 5,286,497; 5,912,013;6,270,805; and 6,322,819. Commercially available modified release coatedactive particles may also be employed. Accordingly, all or a portion ofone or more active ingredients may be coated with a release-modifyingmaterial.

The active ingredient or ingredients may be present in the dosage formin any form. For example, the active ingredient may be dispersed at themolecular level, e.g. melted or dissolved, within the dosage form, ormay be in the form of particles, which in turn may be coated oruncoated. If the active ingredient is in form of particles, theparticles (whether coated or uncoated) typically have an averageparticle size of about 1-2000 microns. In one preferred embodiment, suchparticles are crystals having an average particle size of about 1-300microns. In another preferred embodiment, the particles are granules orpellets having an average particle size of about 50-2000 microns,preferably about 50-1000 microns, most preferably about 100-800 microns.

The first portion of the dosage form is prepared by molding. The firstportion may have any shape that can be molded, and has an area of itssurface that is in contact with the second portion of the dosage form.Preferably, a substantial proportion of the surface area of one entireface of the first molded portion has a shape which is defined by theshape of the second portion.

The second portion of the dosage form may be prepared by any suitablemethod, for example it may be molded or compressed. In one embodiment,the second portion has one or more major faces. If the second portion ismolded, it may have any shape that can be molded.

Molded shapes which may be used for the first portion or second portion(if molded) include a truncated cone; a polyhedron, such as a cube,pyramid, prism, or the like; or a shape having the geometry of a spacefigure with some non-flat faces, such as a cone, cylinder, sphere,torus, or the like.

If the second portion is compressed, it may have any shape that can becompressed. Suitable shapes for compressed dosage forms include tabletshapes formed from compression tooling shapes described by “TheElizabeth Companies Tablet Design Training Manual” (Elizabeth CarbideDie Co., Inc., p.7 (McKeesport, Pa.) (incorporated herein by reference)as follows (the tablet shape corresponds inversely to the shape of thecompression tooling):

-   -   1. Shallow Concave.    -   2. Standard Concave.    -   3. Deep Concave.    -   4. Extra Deep Concave.    -   5. Modified Ball Concave.    -   6. Standard Concave Bisect.    -   7. Standard Concave Double Bisect.    -   8. Standard Concave European Bisect.    -   9. Standard Concave Partial Bisect.    -   10. Double Radius.    -   11. Bevel & Concave.    -   12. Flat Plain.    -   13. Flat-Faced-Beveled Edge (F.F.B.E.).    -   14. F.F.B.E. Bisect.    -   15. F.F.B.E. Double Bisect.    -   16. Ring.    -   17. Dimple.    -   18. Ellipse.    -   19. Oval.    -   20. Capsule.    -   21. Rectangle.    -   22. Square.    -   23. Triangle.    -   24. Hexagon.    -   25. Pentagon.    -   26. Octagon.    -   27. Diamond.    -   28. Arrowhead.    -   29. Bullet.    -   30. Barrel.    -   31. Half Moon.    -   32. Shield.    -   33. Heart.    -   34. Almond.    -   35. House/Home Plate.    -   36. Parallelogram.    -   37. Trapezoid.    -   38. FIG. 8/Bar Bell.    -   39. Bow Tie.    -   40. Uneven Triangle.

The surface of one or more faces of the second portion may besubstantially smooth, i.e. may have indentations or protrusions only atthe microscopic level on the order of less than about 20 microns inwidth, depth, or height. Alternately the surface of one or more facesthe second portion may be textured, i.e. having indentations orprotrusions greater than about 20 microns, e.g. greater than about 50microns, or greater than about 100 microns, or from about 1000 micronsto about 30,000 microns in width, depth, or height. In embodimentswherein the surface of one or more faces the second portion is textured,the surface may contain an embossed (raised) or debossed (indented)design. For example, the surface of one or more faces the second portionmay contain indentations, intagliations, letters, symbols or a patternsuch as a graphic or logo. Alternatively, one or more faces of thesecond portion may contain one or more depressions covering asubstantial proportion of its surface area, for example at least about10%, or at least about 20% or at least about 30% or at least about 50%of the surface area of the face. One type of compressed tablets withindentations in a major face are described for example in WO 01/85437,which describes a process for the production of tablets with a cavityusing a press. WO 99/6157 describes tablets, compressed from aparticulate material, having cavities to receive an additionalingredient or mix of ingredients.

In one embodiment of the invention, a surface of the first moldedportion resides substantially conformally upon a surface of the secondportion. As used herein, “substantially conformally” means that asurface of the first molded portion substantially conforms inversely tothe shape and texture of a surface of the second portion, such that thefirst and second portions are in substantial contact at the interfacebetween them. As used herein, “substantial contact” means that a majorportion of the surface area of at least one surface of the first portionis in contact with a major portion of the surface area of at least onesurface of the second portion.

The dosage form of the invention may also incorporate pharmaceuticallyacceptable adjuvants, including, for example, preservatives, sweetenerssuch as aspartame, acesulfame potassium, sucralose, and saccharin;flavors, antioxidants, surfactants, and coloring agents.

In one embodiment, the dissolution characteristics of at least oneactive ingredient meets USP specifications for immediate release tabletscontaining the active ingredient. In embodiments in which it is desiredfor the active ingredient to be absorbed into the systemic circulationof an animal, the active ingredient or ingredients are preferablycapable of dissolution upon contact with a fluid such as water, gastricfluid, intestinal fluid or the like. For example, for acetaminophentablets, USP 24 specifies that in pH 5.8 phosphate buffer, using USPapparatus 2 (paddles) at 50 rpm, at least 80% of the acetaminophencontained in the dosage form is released therefrom within 30 minutesafter dosing, and for ibuprofen tablets, USP 24 specifies that in pH 7.2phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least80% of the ibuprofen contained in the dosage form is released therefromwithin 60 minutes after dosing. See USP 24, 2000 Version, 19-20 and 856(1999). In another embodiment, the dissolution characteristics of atleast one active ingredient are modified: e.g. controlled, sustained,extended, retarded, prolonged, delayed and the like. In one particularembodiment, one portion of the dosage form provides for immediaterelease of a first dose of an active ingredient therefrom, and the otherportion of the dosage form provides for modified release of a seconddose of either the same or a different active ingredient containedtherein.

The first portion of the dosage form of this invention comprises amolded material. In a preferred embodiment, the molded material may beobtained from flowable material. The flowable material may be any ediblematerial that is flowable at a temperature between about 37° C. and 250°C., and that is solid or can form a gel at a temperature between about−10° C. and about 35° C. When it is in the fluid or flowable state, theflowable material may comprise a dissolved or molten component, and asolvent such as for example water. The solvent may be partially orsubstantially removed by drying. Suitable flowable materials includethose comprising film forming polymers, gelling polymers, hydrocolloids,low melting hydrophobic materials such as fats and waxes,non-crystallizable carbohydrates, and the like.

In one embodiment of the invention, the flowable material comprisesgelatin. Gelatin is a natural, thermogelling polymer. It is a tastelessand colorless mixture of derived proteins of the albuminous class whichis ordinarily soluble in warm water. Two types of gelatin—Type A andType B—are commonly used. Type A gelatin is a derivative of acid-treatedraw materials. Type B gelatin is a derivative of alkali-treated rawmaterials. The moisture content of gelatin, as well as its Bloomstrength, composition and original gelatin processing conditions,determine its transition temperature between liquid and solid. Bloom isa standard measure of the strength of a gelatin gel, and is roughlycorrelated with molecular weight. Bloom is defined as the weight ingrams required to move a half-inch diameter plastic plunger 4 mm into a6.67% gelatin gel that has been held at 10° C. for 17 hours. In apreferred embodiment, the flowable material is an aqueous solutioncomprising 20% 275 Bloom pork skin gelatin, 20% 250 Bloom Bone Gelatin,and approximately 60% water.

Other preferred flowable materials may comprise sucrose-fatty acidesters; fats such as cocoa butter, hydrogenated vegetable oil such aspalm kernel oil, cottonseed oil, sunflower oil, and soybean oil; mono-di- and triglycerides, phospholipids, waxes such as carnuba wax,spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystallinewax, and paraffin wax; fat-containing mixtures such as chocolate; sugarin the form on an amorphous glass such as that used to make hard candyforms, crystallized sugar in a supersaturated solution such as that usedto make fondant forms; carbohydrates such as sugar-alcohols (forexample, sorbitol, maltitol, mannitol, xylitol), or thermoplasticstarch; and low-moisture polymer solutions such as mixtures of gelatinand other hydrocolloids at water contents up to about 30%, such as forexample those used to make “gummi” confection forms.

In one embodiment of the invention, the flowable material may comprise afilm former such as a cellulose ether, e.g. hydroxypropylmethylcelluloseor a modified starch, e.g. waxy maize starch; optionally an extender,such as polycarbohydrates, e.g. polydextrose or maltodextrin; optionallya thickener, such as a hydrocolloid, e.g. xanthan gum or carrageenan, ora sugar, e.g. sucrose; optionally a plasticizer, e.g. polyethyleneglycol, propylene glycol, vegetable oils such as castor oil, glycerin,and mixtures thereof.

Any film former known in the art is suitable for use in the flowableshell material of the present invention. Examples of suitable filmformers include, but are not limited to, polyvinylalcohol (PVA),polyvinylpyrrolidone (PVP), hydroxypropyl starch, hydroxyethyl starch,pullulan, methylethyl starch, carboxymethyl starch, methylcellulose,hydroxypropylcellulose (HPC), hydroxyethylmethylcellulose (HEMC),hydroxypropylmethylcellulose (HPMC), hydroxybutylmethylcellulose (HBMC),hydroxyethylethylcellulose (HEEC), hydroxyethylhydroxypropylmethylcellulose (HEMPMC), methacrylic acid and methacrylate ester copolymers,polyethylene oxide and polyvinylpyrrolidone copolymers, gelatin,proteins such as whey protein, coaggulatable proteins such as albumin,casein, and casein isolates, soy protein and soy protein isolates,pre-gelatinized starches, and polymers and derivatives and mixturesthereof.

One suitable hydroxypropylmethylcellulose compound is HPMC 2910, whichis a cellulose ether having a degree of substitution of about 1.9 and ahydroxypropyl molar substitution of 0.23, and containing, based upon thetotal weight of the compound, from about 29% to about 30% methoxyl andfrom about 7% to about 12% hydroxylpropyl groups. HPMC 2910 iscommercially available from the Dow Chemical Company under the tradenameMETHOCEL E. METHOCEL E5, which is one grade of HPMC-2910 suitable foruse in the present invention, has a viscosity of about 4 to 6 cps (4 to6 millipascal-seconds) at 20° C. in a 2% aqueous solution as determinedby a Ubbelohde viscometer. Similarly, METHOCEL E6, which is anothergrade of HPMC-2910 suitable for use in the present invention, has aviscosity of about 5 to 7 cps (5 to 7 millipascal-seconds) at 20° C. ina 2% aqueous solution as determined by a Ubbelohde viscometer. METHOCELE15, which is another grade of HPMC-2910 suitable for use in the presentinvention, has a viscosity of about 15000 cps (15 millipascal-seconds)at 20° C. in a 2% aqueous solution as determined by a Ubbelohdeviscometer. As used herein, “degree of substitution” shall mean theaverage number of substituent groups attached to a anhydroglucose ring,and “hydroxypropyl molar substitution” shall mean the number of moles ofhydroxypropyl per mole anhydroglucose.

As used herein, “modified starches” include starches that have beenmodified by crosslinking, chemically modified for improved stability, orphysically modified for improved solubility properties. As used herein,“pre-gelatinized starches” or “instantized starches” refers to modifiedstarches that have been pre-wetted, then dried to enhance theircold-water solubility. Suitable modified starches are commerciallyavailable from several suppliers such as, for example, A. E. StaleyManufacturing Company, and National Starch & Chemical Company. Onesuitable modified starch includes the pre-gelatinized waxy maizederivative starches that are commercially available from National Starch& Chemical Company under the tradenames PURITY GUM and FILMSET, andderivatives, copolymers, and mixtures thereof. Such waxy maize starchestypically contain, based upon the total weight of the starch, from about0 percent to about 18 percent of amylose and from about 100% to about88% of amylopectin.

Suitable tapioca dextrins include those available from National Starch &Chemical Company under the tradename CRYSTAL GUM or K-4484, andderivatives thereof such as modified food starch derived from tapioca,which is available from National Starch and Chemical under the tradenamePURITY GUM 40, and copolymers and mixtures thereof.

Any thickener known in the art is suitable for use in the film formingcomposition of the present invention. Examples of such thickenersinclude but are not limited to hydrocolloids (also referred to herein asgelling polymers) such as alginates, agar, guar gum, locust bean,carrageenan, tara, gum arabic, tragacanth, pectin, xanthan, gellan,maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gumarabic, inulin, pectin, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan, and derivatives and mixtures thereof. Additionalsuitable thickeners include crystallizable sugars, such as glucose(dextrose), fructose, and the like, and derivatives and combinationsthereof.

Suitable xanthan gums include those available from C. P. Kelco Companyunder the tradename, KELTROL 1000, XANTROL 180, or K9B310.

Any plasticizer known in the pharmaceutical art is suitable for use inthe present invention, and may include, but not be limited topolyethylene glycol; glycerin; sorbitol; triethyl citrate; tribuylcitrate; dibutyl sebecate; vegetable oils such as castor oil;surfactants such as polysorbates, sodium lauryl sulfates, anddioctyl-sodium sulfosuccinates; propylene glycol; mono acetate ofglycerol; diacetate of glycerol; triacetate of glycerol; natural gumsand mixtures thereof. In solutions containing a cellulose ether filmformer, an optional plasticizer may be present in an amount, based uponthe total weight of the solution, from about 0% to about 40%.

The flowable material may optionally comprise adjuvants or excipients,in which may comprise up to about 20% by weight of the flowablematerial. Examples of suitable adjuvants or excipients includedetackifiers, humectants, surfactants, anti-foaming agents, colorants,flavorants, sweeteners, opacifiers, and the like. In one preferredembodiment, the flowable material comprises less than 5% humectants, oralternately is substantially free of humectants, such as glycerin,sorbitol, maltitol, xylitol, or propylene glycol. Humectants havetraditionally been included in pre-formed films employed in enrobingprocesses, such as that disclosed in U.S. Pat. Nos. 5,146,730 and5,459,983, to ensure adequate flexibility or plasticity and bondabilityof the film during processing. Humectants function by binding water andretaining it in the film. Pre-formed films used in enrobing processescan typically comprise up to 45% water. Disadvantageously, the presenceof humectant prolongs the drying process, and can adversely affect thestability of the finished dosage form.

In a preferred embodiment of the invention, the molded materialcomprises at least about 80%; e.g. at least about 90% of a materialselected from film formers, gelling polymers (hydrocolloids),low-melting hydrophobic materials, non-crystallizable carbohydrates, andmixtures thereof. The molded material may be formed by injectionmolding, advantageously minimizing or eliminating the need fordirect-compression filler-binders such as microcrystalline cellulose,spray-dried lactose, mineral salts such as calcium phosphate,crystalline sugars such as sucrose, dextrates and the like. Thesematerials would disadvantageously detract from the clarity and stabilityof the molded material. Preferably the molded material comprises lessthan about 10%, e.g. less than about 1%, or less than about 0.1% ofdirect-compression filler-binders.

In another embodiment, the molded material is prepared by thermalsetting molding using the method and apparatus described in copendingU.S. patent application Ser. No. 09/966,450, pages 57-63, the disclosureof which is incorporated herein by reference. In this embodiment, themolded material is formed by injecting a starting material in flowableform into a molding chamber. The starting material preferably comprisesan active ingredient and a thermal setting material at a temperatureabove the melting point of the thermal setting material but below thedecomposition temperature of the active ingredient. The startingmaterial is cooled and solidifies in the molding chamber into a shapedform (i.e. having the shape of the mold).

In another embodiment, the molded material is prepared by thermal cyclemolding using the method and apparatus described in copending U.S.patent application Ser. No. 09/966,497, pages 27-51, the disclosure ofwhich is incorporated herein by reference. In this embodiment, themolded material is formed by injecting a starting material in flowableform into a heated molding chamber. The starting material preferablycomprises an active ingredient and a thermoplastic material at atemperature above the set temperature of the thermoplastic material butbelow the decomposition temperature of the active ingredient. Thestarting material is cooled and solidifies in the molding chamber into ashaped form (i.e., having the shape of the mold).

According to this method, the starting material must be in flowableform. For example, it may comprise solid particles suspended in a moltenmatrix, for example a polymer matrix. The starting material may becompletely molten or in the form of a paste. The starting material maycomprise an active ingredient dissolved in a molten material.Alternatively, the starting material may be made by dissolving a solidin a solvent, which solvent is then evaporated from the startingmaterial after it has been molded.

The starting material may comprise any edible material which isdesirable to incorporate into a shaped form, including activeingredients such as those active ingredients described herein,nutritionals, vitamins, minerals, flavors, sweeteners, and the like.Preferably, the starting material comprises an active ingredient and athermal setting material. The thermal setting material may be any ediblematerial that is flowable at a temperature between about 37 to about250° C., and that is a solid at a temperature between about 0 to about−10° C. Preferred thermal setting materials include water-solublepolymers such as polyalkylene glycols, polyethylene oxides andderivatives, and sucrose esters; fats such as cocoa butter, hydrogenatedvegetable oil such as palm kernel oil, cottonseed oil, sunflower oil,and soybean oil; mono- di- and triglycerides, phospholipids, waxes suchas carnuba wax, spermaceti wax, beeswax, candelilla wax, shellac wax,microcrystalline wax, and paraffin wax; fat-containing mixtures such aschocolate; sugar in the form on an amorphous glass such as that used tomake hard candy forms, crystallized carbohydrates in a supersaturatedsolution such as that used to make fondant forms; low-moisture polymersolutions such as mixtures of gelatin and other hydrocolloids at watercontents up to about 30% such as those used to make “gummi” confectionforms. In a particularly preferred embodiment, the thermal settingmaterial is a water-soluble polymer such as polyethylene glycol.

The first portion may be made in any shape or size. For instance,irregularly shaped first portions may be made; i.e. shapes having nomore than one axis of symmetry. Cylindrically shaped first portions mayalso be made. The molded material may be prepared by any molding method,such as injection molding. In a preferred embodiment, the moldedmaterial may be made using the thermal setting method and apparatusdescribed herein. In another preferred embodiment of the invention, themolded material is prepared by thermal cycle molding as describedherein.

The first molded material and second material of the dosage form of thisinvention are compositionally different. As used herein, the term“compositionally different” means having features that are readilydistinguishable by qualitative or quantitative chemical analysis,physical testing, or visual observation. For example, the first andsecond materials may contain different ingredients, or different levelsof the same ingredients, or the first and second materials may havedifferent physical or chemical properties, different functionalproperties, or be visually distinct. Examples of physical or chemicalproperties that may be different include hydrophylicity, hydrophobicity,hygroscopicity, elasticity, plasticity, tensile strength, crystallinity,and density. Examples of functional properties which may be differentinclude rate and/or extent of dissolution of the material itself or ofan active ingredient therefrom, rate of disintegration of the material,permeability to active ingredients, permeability to water or aqueousmedia, and the like. Examples of visual distinctions include size,shape, topography, or other geometric features, color, hue, opacity, andgloss.

In one embodiment, the second portion of the dosage form of thisinvention comprises a compressed material. In one preferred embodimentof this invention, the second portion is obtained by compressing apowder. The powder may preferably comprise an active ingredient andoptionally contain various excipients, such as binders, disintegrants,lubricants, fillers, glidants and the like, as is conventional, or otherparticulate material of a medicinal or non-medicinal nature, such asinactive placebo blends for tableting, confectionery blends, and thelike. In one embodiment, the compressed second portion comprises activeingredient, powdered wax (such as shellac wax, microcrystalline wax,polyethylene glycol, and the like), and optionally disintegrants andlubricants as are well known to those skilled in the art.

In one embodiment of the invention, the second portion is obtained froma blend of powders having an average particle size of about 50 to about500 microns. In one embodiment, the active ingredient has an averageparticle size of about 50 to about 500 microns. In another embodiment,at least one excipient has an average particle size of about 50 to about500 microns. In one such embodiment, a major excipient, i.e. andexcipient comprising at least 50% by weight of the core, has an averageparticle size of about 50 to about 500 microns. Particles in this sizerange are particularly useful for direct compression processes.

In another embodiment of the invention, the second portion is a directlycompressed tablet, made from a powder which is substantially free ofwater soluble polymeric binders and hydrated polymers. This compositionis advantageous for maintaining an immediate release dissolutionprofile, minimizing processing and material costs, and providing foroptimal physical and chemical stability of the dosage form.

Suitable excipients for use in a compressed portion include fillers,binders, disintegrants, lubricants, glidants, and the like.

Suitable fillers include water-soluble compressible carbohydrates suchas sugars, which include dextrose, sucrose, maltose, and lactose,sugar-alcohols, which include mannitol, sorbitol, maltitol, xylitol,starch hydrolysates, which include dextrins, and maltodextrins, and thelike, water insoluble plasticly deforming materials such asmicrocrystalline cellulose or other cellulosic derivatives,water-insoluble brittle fracture materials such as dicalcium phosphate,tricalcium phosphate and the like and mixtures thereof.

Suitable binders include dry binders such as polyvinyl pyrrolidone,hydroxypropylmethylcellulose, and the like; wet binders such aswater-soluble polymers, including hydrocolloids such as alginates, agar,guar gum, locust bean, carrageenan, tara, gum arabic, tragacanth,pectin, xanthan, gellan, maltodextrin, galactomannan, pusstulan,laminarin, scleroglucan, gum arabic, inulin, pectin, whelan, rhamsan,zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinylpyrrolidone, cellulosics, starches, and the like; and derivatives andmixtures thereof.

Suitable disintegrants include sodium starch glycolate, cross-linkedpolyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches,microcrystalline cellulose, and the like.

Suitable lubricants include long chain fatty acids and their salts, suchas magnesium stearate and stearic acid, talc, and waxes.

Suitable glidants include colloidal silicon dioxide, and the like.

In a preferred embodiment, the second portion is prepared by thecompression methods and apparatus described in copending U.S.application Ser. No. 09/966,509, pages 16-27, the disclosure of which isincorporated herein by reference. Specifically, the second portion ismade using a rotary compression module comprising a fill zone, insertionzone, compression zone, ejection zone, and purge zone in a singleapparatus having a double row die construction as shown in FIG. 6 ofU.S. application Ser. No. 09/966,509. The dies of the compression moduleare preferably filled using the assistance of a vacuum, with filterslocated in or near each die. The purge zone of the compression moduleincludes an optional powder recovery system to recover excess powderfrom the filters and return excess powder to the dies.

In another embodiment of the invention, the first or second portions, orboth, may contain at least in part one or more inserts. The inserts canbe made in any shape or size. For instance, irregularly shaped insertscan be made; i.e. shapes having no more than one axis of symmetry.Cylindrically shaped inserts may also be made. The insert may beprepared using conventional techniques such as panning, compression, ormolding. In one embodiment, the insert is prepared using the thermalsetting method and apparatus as described herein.

In one embodiment of the invention, the insert or inserts may have anaverage diameter from about 100 to about 1000 microns. In anotherembodiment of this invention, the insert(s) may have an average diameteror thickness from about 10% to about 90% of the diameter or thickness ofthe dosage form, or portion thereof. In yet another embodiment of thisinvention, the first or second dosage form portion may comprise aplurality of inserts.

In another embodiment of the invention, the first portion, secondportion, or both may comprise a microelectronic device (e.g. anelectronic “chip”) which may be used as an active component or tocontrol, for example, the rate of release of active ingredientscontained within the first and/or second portions or insert in responseto an input signal. Examples of such microelectronic devices are asfollows:

-   -   (1) Integrated, self-regulating responsive therapeutic devices        including biosensors, electronic feedback and        drug/countermeasure release devices which are fully integrated.        Such devices eliminate the need for telemetry and human        intervention, and are disclosed, for example, at        www.chiprx.com/products.html, which is incorporated herein by        reference;    -   (2) Miniaturized diagnostic imaging systems which comprise a        swallowable capsule containing a video camera, and are        disclosed, for example, at www.givenimaging.com/usa/default.asp,        which is incorporated herein by reference;    -   (3) Subcutaneous glucose monitors which comprise implantable or        insertable sensor devices which detect changes in glucose        concentration within intestinal fluid, and communicate to an        external detector and data storage device. Such devices are        disclosed, for example, at        www.applied-medical.co.uk/glucose.htm, which is incorporated        herein by reference;    -   (4) Microdisplay vision aid devices encapsulated in an        artificial intraocular lens. Such devices include a receiver for        power supply, data and clock recovery, and a miniature LED array        flip-chip bonded to a silicon CMOS driver circuit and micro        optics, and are disclosed, for example, at        http://ios.oe.uni-duisberg.de/e/, which is incorporated herein        by reference. The microdisplay device receives a        bit-stream+energy wireless signal from a high dynamic range CMOS        camera placed outside the eye which generates a digital black &        white picture which is converted by a digital signal processing        unit (DAP) into a serial bit-stream with a data rate of        approximately 1 Mbit/s. The image is projected onto the retina;    -   (5) Microchips used to stimulate damaged retinal cells, allowing        them to send visual signals to the brain for patients with        macular degeneration or other retinal disorders. The chip is 2        mm×25 microns, and contains approximately 5,000 microscopic        solar cells (“microphotodiodes”), each with its own stimulating        electrode. These microphotodiodes convert the light energy from        images into electrical chemical impulses that stimulate the        remaining functional cells of the retina in patients with AMD        and RP. Such microchips are disclosed, for example, at        www.optobionics.com/artificialretina.htm, which is incorporated        herein by reference;    -   (6) Disposable “smart needles” for breast biopsies which display        results in real time. The device fits into a 20 to 21 gauge        disposable needle that is connected to a computer, as the needle        is inserted into the suspicious lesion. The device measures        oxygen partial pressure, electrical impedance, temperature, and        light scattering and absorption properties including        deoxygenated hemoglobin, vascularization, and tissue density.        Because of the accuracy benefits from the six simultaneous        measurements, and real-time nature of the device, it is expected        to exceed the accuracy levels achieved by the core needle biopsy        procedure and approach the high level of accuracy associated        with surgical biopsies. Further, if cancer is found, the device        can be configured to deliver various therapies such as cancer        markers, laser heat, cryogenics, drugs, and radioactive seeds.        Such devices are disclosed, for example, at        www.bioluminate.com/description.html, which is incorporated        herein by reference; and    -   (7) Personal UV-B recorders, which are instrument grade devices        for measuring and recording UVB exposure and fit into a        wrist-watch face. They may also be worn as a patch.

In one preferred embodiment, the invention provides a dosage formcomprising a thermal cycle molded first portion and a compressed powdersecond portion.

In another preferred embodiment, the invention provides a dosage formcomprising an injection molded first portion and a compressed powdersecond portion.

In one embodiment of the invention, only the first portion comprises oneor more active ingredients. In another embodiment of this invention,only the second portion comprises one or more active ingredients. In yetanother embodiment of this invention, only the insert or insertscomprise one or more active ingredients. In yet another embodiment ofthis invention, both the first and second portions comprise one or moreactive ingredients. In yet another embodiment of this invention, one ormore of the first portion, second portion or the insert or insertscomprise one or more of the active ingredients. The active ingredient oringredients are preferably capable of dissolution upon contact with afluid such as water, gastric fluid, intestinal fluid or the like.

In embodiments wherein one portion of the dosage form comprises activeingredients, and another portion of the dosage form is substantiallyfree of active ingredients, the invention advantageously enables asystem of dosage form design with the versatility to accomodate multipledifferent dosage amounts of medication in the same size tablet, yet bereadily identifiable to patients and healthcare professionals in termsof its identity and strength. For example, a particular medication maybe commercially available in several different strength dosage forms. Itis possible to design, using the present invention, a series of dosageforms in which the second portion comprises active ingredient, andvaries in size according to the amount of active ingredient containedtherein. The molded first portion of the dosage form may besubstantially free of active ingredient, and may vary in size inverselyaccording the the size of the first portion, such that the overall sizeof the dosage form remains constant for the different strengths ofactive ingredient contained therein. In one such embodiment, the twoportions of the dosage forms may be visually distinct. For example, thesecond portion of the dosage form may be colored and/or opaque, and thefirst portion of the dosage form may be colorless, transparent,semi-transparent or translucent, thus providing visual reinforcement toboth healthcare professionals and patients as to the varying strengthsof the available dosage forms.

An overall understanding of the dosage form of this invention may beobtained by reference to FIGS. 1A and 1B. In FIGS. 1A and 1B, a dosageform 2 is depicted which comprises a first portion 8 comprising a moldedmaterial 10 and a second portion 4 comprising a compressed material 6.Material 10 and material 6 are compositionally different. It will beunderstood that the shapes of the first and second portions in FIGS. 1Aand 1B are merely illustrative, and are not meant to limit thisinvention in any way.

Another embodiment of the invention is depicted in FIGS. 2A and 2B, inwhich a dosage form 22 is depicted which comprises a first portion 24comprising a first molded material 26 and a second molded material 27,and a second portion 28 comprising a compressed material 30. Materials26 and 27 are each are compositionally different from material 30. Itwill be understood that the shapes of the first and second portions inFIGS. 2A and 2B are merely illustrative, and are not meant to limit thisinvention in any way.

Another embodiment of the invention is depicted in FIGS. 3A and 3B, inwhich dosage form 32 is depicted which comprises a first portion 34comprising a molded material 36, and a second portion 38 (shown indashed outline in FIG. 3A) comprising a compressed material 40. Material36 is compositionally different from material 40. It will be understoodthat the shapes of the first and second portions in FIGS. 3A and 3B aremerely illustrative, and are not meant to limit this invention in anyway.

Another embodiment of the invention is depicted in FIGS. 4A and 4B, inwhich dosage form 42 is depicted which comprises a first portion 44comprising a first molded material 46, and a second portion 48 which isa molded insert which comprises a second molded material 50. Material 46is compositionally different from material 50. It will be understoodthat the shapes of the first and second portions in FIGS. 4A and 4B aremerely illustrative, and are not meant to limit this invention in anyway.

Another embodiment of the invention is depicted in FIGS. 5A and 5B, inwhich dosage form 52 is depicted which comprises a first portion 54comprising a molded material 56, and a second portion 58 comprising acompressed material 60. Material 56 is compositionally different frommaterial 60. It will be understood that the shapes of the first andsecond portions in FIGS. 5A and 5B are merely illustrative, and are notmeant to limit this invention in any way.

Another embodiment of the invention is depicted in FIGS. 6A and 6B, inwhich dosage form 62 is depicted which comprises a first portion 64comprising a molded material 66, and a second portion 68 comprising acompressed material 70. Material 66 is compositionally different frommaterial 70. It will be understood that the shapes of the first andsecond portions in FIGS. 6A and 6B are merely illustrative, and are notmeant to limit this invention in any way.

Another embodiment of the invention is depicted in FIGS. 7A-7C, in whichdosage form 72 is depicted which comprises a first portion 74 comprisinga molded material 76, and a second portion 78 comprising a compressedmaterial 80. Material 76 is compositionally different from material 70.As shown in FIGS. 7B and 7C, first portion 74 has projections 75 on oneface thereof. It will be understood that the shapes of the first andsecond portions in FIGS. 7A-7C are merely illustrative, and are notmeant to limit this invention in any way.

Other embodiments of the invention are depicted in FIGS. 8A-8C. In FIG.8A, dosage form 82 is depicted which comprises a first portion 84comprising a molded material 86, and a second portion 88 comprising acompressed material 90. Material 86 is compositionally different frommaterial 90. In FIG. 8B, dosage form 182 is depicted which comprises afirst portion 184 comprising a molded material 186, and a second portion188 comprising a compressed material 190. Material 186 iscompositionally different from material 190. As shown in FIG. 8B, firstportion 184 has a tongue shaped portion 183 which interfaces with grooveshaped portion 185 of second portion 188. In FIG. 8C, dosage form 282 isdepicted which comprises a first portion 284 comprising a moldedmaterial 286, and a second portion 288 comprising a compressed material290. Material 286 is compositionally different from material 290. Itwill be understood that the shapes of the first and second portions inFIGS. 8A-8C are merely illustrative, and are not meant to limit thisinvention in any way.

Another embodiment of the invention is depicted in FIGS. 9A and 9B, inwhich dosage form 92 is depicted which comprises a first portion 94comprising a molded material 96, and a second portion 98 comprising acompressed material 100. Material 96 is compositionally different frommaterial 100. It will be understood that the shapes of the first andsecond portions in FIGS. 9A and 9B are merely illustrative, and are notmeant to limit this invention in any way.

Another embodiment of this invention is depicted in FIG. 10, in whichdosage form 102 is depicted which comprises a first portion 104comprising a molded material 106, a second portion 108 comprising acompressed material 105, and a third portion 107 which may comprise amolded or compressed material 109, preferably a molded material.Material 106 is compositionally different from material 105. Material109 may be compositionally the same or different than materials 106 or105, although in the embodiment depicted in FIG. 10 each of materials106, 105 and 109 is compositionally different from each other. In thisembodiment, either first portion 104 or second portion 108 or bothcontain an active ingredient. Third portion 107 may act as a barrier toprevent the passage there through of either or both the activeingredients contained in first portion 104 or second portion 108. Itwill be understood that the shapes of the first, second and thirdportions in FIG. 10 are merely illustrative, and are not meant to limitthis invention in any way.

In one embodiment, the third portion has one or more major faces. Thethird portion may be prepared by any suitable method, for example it maybe molded or compressed. The third portion may have a variety of moldedshapes, as described above with respect to the first and secondportions.

In one particular embodiment, the invention is a bi-layer tablet inwhich the second portion is a compressed layer, the first portion is amolded layer, and the interface between the compressed and moldedportions is a major tablet face.

The first molded material is substantially free of pores having adiameter of 0.5-5.0 microns. As used herein, “substantially free” meansthat the first molded material has a pore volume of less than about 0.02cc/g, preferably less than about 0.01 cc/g, more preferably less thanabout 0.005 cc/g, in the pore diameter range of 0.5 to 5.0 microns.Typical compressed materials have pore volumes of more than about 0.02cc/g in this pore diameter range. In embodiments of this invention inwhich the second or third portions comprise a molded material, themolded material contained in the second or third portion likewise issubstantially free of pores having a diameter of 0.5 to 5.0 microns.Pore volume, pore diameter and density may be determined using aQuantachrome Instruments PoreMaster 60 mercury intrusion porosimeter andassociated computer software program known as “Porowin.” The procedureis documented in the Quantachrome Instruments PoreMaster OperationManual. The PoreMaster determines both pore volume and pore diameter ofa solid or powder by forced intrusion of a non-wetting liquid (mercury),which involves evacuation of the sample in a sample cell (penetrometer),filling the cell with mercury to surround the sample with mercury,applying pressure to the sample cell by: (i) compressed air (up to 50psi maximum); and (ii) a hydraulic (oil) pressure generator (up to 60000psi maximum). Intruded volume is measured by a change in the capacitanceas mercury moves from outside the sample into its pores under appliedpressure. The corresponding pore size diameter (d) at which theintrusion takes place is calculated directly from the so-called“Washburn Equation”: d=−(4γ(cos Ø))/P where γ is the surface tension ofliquid mercury, Ø is the contact angle between mercury and the samplesurface and P is the applied pressure.

Equipment used for pore volume measurements:

-   -   1. Quantachrome Instruments PoreMaster 60.    -   2. Analytical Balance capable of weighing to 0.0001 g.    -   3. Desiccator.

Reagents used for measurements:

-   -   1. High purity nitrogen.    -   2. Triply distilled mercury.    -   3. High pressure fluid (Dila AX, available from Shell Chemical        Co.).    -   4. Liquid nitrogen (for Hg vapor cold trap).    -   5. Isopropanol or methanol for cleaning sample cells.    -   6. Liquid detergent for cell cleaning.

Procedure:

The samples remain in sealed packages or as received in the dessicatoruntil analysis. The vacuum pump is switched on, the mercury vapor coldtrap is filled with liquid nitrogen, the compressed gas supply isregulated at 55 psi., and the instrument is turned on and allowed a warmup time of at least 30 minutes. The empty penetrometer cell is assembledas described in the instrument manual and its weight is recorded. Thecell is installed in the low pressure station and “evacuation and fillonly” is selected from the analysis menu, and the following settings areemployed:

-   -   Fine Evacuation time: 1 min.    -   Fine Evacuation rate: 10    -   Coarse Evacuation time: 5 min.

The cell (filled with mercury) is then removed and weighed. The cell isthen emptied into the mercury reservoir, and two tablets from eachsample are placed in the cell and the cell is reassembled. The weight ofthe cell and sample are then recorded. The cell is then installed in thelow-pressure station, the low-pressure option is selected from the menu,and the following parameters are set:

-   -   Mode: Low pressure    -   Fine evacuation rate: 10    -   Fine evacuation until: 200% Hg    -   Coarse evacuation time: 10 min.    -   Fill pressure: Contact +0.1    -   Maximum pressure: 50    -   Direction: Intrusion And Extrusion    -   Repeat: 0    -   Mercury contact angle; 140    -   Mercury surface tension: 480

Data acquisition is then begun. The pressure vs. cumulativevolume-intruded plot is displayed on the screen. After low-pressureanalysis is complete, the cell is removed from the low-pressure stationand reweighed. The space above the mercury is filled with hydraulic oil,and the cell is assembled and installed in the high-pressure cavity. Thefollowing settings are used:

-   -   Mode: Fixed rate    -   Motor speed: 5    -   Start pressure: 20    -   End pressure: 60,000    -   Direction: Intrusion and extrusion    -   Repeat: 0    -   Oil fill length: 5    -   Mercury contact angle: 140    -   Mercury surface tension: 480

Data acquisition is then begun and graphic plot pressure vs. intrudedvolume is displayed on the screen. After the high pressure run iscomplete, the low-and high-pressure data files of the same sample aremerged.

In another embodiment of this invention, the composite dosage form ofthe present invention may be coated with an overcoating or shell.

In another embodiment of this invention, at least part of the firstportion extends below or penetrates through a surface of the secondportion to define a penetrated surface area of the second portion. Thearea of the interface surfaces is substantially the same, preferably atleast 90%, of the penetrated surface area.

In another embodiment of this invention, the area of the interfacesurfaces is at least 10%, preferably 25%, more preferably at least 50%,say greater than 90% of the area of a major face of either the first orsecond portions.

In another embodiment of this invention, one face or side of the secondportion comprises a cavity, and the first portion is in contact with theentire surface of the cavity.

A particular advantage of the present invention is that either the firstmolded portion or second portion may be larger in cross-section (in atleast one location) than the opening to the cavity within the secondportion or first molded portion, respectively, which receives the firstportion or second portion. In contrast, in the prior art an insert mustbe no larger in cross-section than the opening of the cavity whichreceives the insert. In a preferred embodiment of this invention, thefirst molded portion or a part thereof is received by a cavity locatedwithin the second portion. Thus, the first molded portion forms a“tongue” which interlocks with the cavity or “groove” within the secondportion. This may also be expressed in terms of the “draft angle” of thesecond portion. As used herein, the term “draft angle” refers to theangle defined by the side wall of the cavity and a line perpindicular tothe face of the inserted (e.g. first) portion, as described for examplein Rosato et al., Injection Molding Handbook, pp. 601-04, (2d ed. 1995),the disclosure of which is incorporated herein by reference. In thepresent invention, the draft angle of the second portion may have avalue less than zero. However, in the prior art compositions, the draftangle must have a zero or positive value.

In another embodiment of this invention, at least one exterior surfaceof the first portion is flush with at least one exterior surface of thesecond portion.

This invention will be further illustrated by the following examples,which are not meant to limit the invention in any way.

EXAMPLE 1

Dosage forms of the invention are made in a continuous process using anapparatus comprising a thermal cycle molding module and a compressionmodule linked in series via a transfer device as described at pages14-16 of copending U.S. application Ser. No. 09/966,939, the disclosureof which is incorporated herein by reference. The dosage forms have thestructure shown in FIGS. 1A and 1B and comprise a first portioncomprising a first molded material and a second portion comprising asecond material that is compressed.

The first portions are made of a flowable material comprising thefollowing ingredients: Weight Mg/ Tablet Trade Name Manufacturer %Tablet Polyethylene Carbowax ® Union Carbide 60.3 190 Glycol 3350Corporation, Danbury, CT Croscarmellose Ac-Di-Sol ® FMC Corporation,30.1 95 Sodium Newark, DE Pseudoephedrine BASF 9.5 30 HydrochloridePharmaChemikalien Crystal GmbH & Co., Ludwigshafen/ Rhein.

The second portions are made of a dry blend comprising the followingingredients: acetaminophen USP (590 mg/tablet), synthetic wax X-2068 T20(53 mg/tablet), sodium starch glycolate (EXPLOTAB) (13.9 mg/tablet),silicon dioxide (0.6 mg/tablet), and magnesium stearate NF (2.4mg/tablet). The dry blend is compressed into second portions on acompression module as described in copending U.S. application Ser. No.09/966,509 at pages 16-27 (incorporated herein by reference). Thecompression module is a double row, rotary apparatus, comprising a fillzone, insertion zone, compression zone, ejection zone, and purge zone asshown in FIG. 6 of U.S. application Ser. No. 09/966,509. The dies of thecompression module are filled using vacuum assistance, with mesh screenfilters located in die wall ports of each die.

Second portions are transferred from the compression module to thethermal cycle molding module via a transfer device. The transfer devicehas the structure shown as 300 in FIG. 3 of copending U.S. applicationSer. No. 09/966,414, described at pages 51-57, incorporated herein byreference. It comprises a plurality of transfer units 304 attached incantilever fashion to a belt 312 as shown in FIGS. 68 and 69 ofcopending U.S. application Ser. No. 09/966,414. The transfer devicerotates and operates in sync with the thermal cycle molding module andcompression module to which it is coupled. Transfer units 304 compriseretainers 330 for holding the second portions as they travel around thetransfer device.

Next, first portions are produced and joined to the second portions inthe thermal cycle molding module, which has the general structure shownin FIG. 3 of copending U.S. application Ser. No. 09/966,497. The thermalcycle molding module 200 comprises a rotor 202 around which a pluralityof mold units 204 are disposed. The thermal cycle molding moduleincludes a reservoir 206 (see FIG. 4 of pending U.S. application Ser.No. 09/966,497) for holding the material for making the first portionsin flowable form. In addition, the thermal cycle molding module isprovided with a temperature control system for rapidly heating andcooling the mold units. FIGS. 55 and 56 of U.S. application Ser. No.09/966,497 depict the temperature control system 600.

The thermal cycle molding module has the specific configuration shown inFIG. 26A of copending U.S. application Ser. No. 09/966,497. The thermalcycle molding module comprises center mold assemblies 212 and upper moldassemblies 214 as shown in FIG. 26C of copending U.S. application Ser.No. 09/966,497, which mate to form mold cavities. As rotor 202 rotates,second portions are loaded into the center mold assemblies, and theopposing center and upper mold assemblies close. Flowable material formaking the first portions, which is heated to a flowable state inreservoir 206, is injected into the resulting mold cavities, whichcontain an empty space adjacent to the second portions. First portionsform in the empty space. The temperature of the flowable material isthen decreased, hardening the flowable material into first portionsjoined to the compressed second portions. The mold assemblies open andeject the dosage forms.

Although this invention has been illustrated by reference to specificembodiments, it will be apparent to those skilled in the art thatvarious changes and modifications may be made which clearly fall withinthe scope of this invention.

1. A dosage form comprising at least one active ingredient, a firstportion comprising a first molded material, and a second portioncomprising a second material which is compositionally different from thefirst material, wherein the first and second portions are joined at aninterface, and a surface of the first portion at the interface residessubstantially conformally upon a surface of the second portion at theinterface.
 2. The dosage form of claim 1, wherein the first portioncomprises a thermoplastic material.
 3. The dosage form of claim 1,wherein the first molded material is substantially free of pores havinga diameter of 0.5 to 5.0 microns.
 4. The dosage form of claim 1, whereinthe first portion comprises a foam.
 5. The dosage form of claim 1,wherein the first portion comprises an aerated material.
 6. The dosageform of claim 1, in which the active ingredient is coated with arelease-modifying coating.
 7. The dosage form of claim 1, in which thefirst and second portions are in substantial contact at the interface.8. The dosage form of claim 1, in which the interface is in the form ofan abutment.
 9. The dosage form of claim 1, in which the first andsecond portions overlap at the interface.
 10. The dosage form of claim1, in which the first and second portions interlock at the interface.11. The dosage form of claim 1, in which the first and second portionsdissociate upon immersion in aqueous media.
 12. The dosage form of claim1, further comprising a third portion, which is located between thefirst and second portions.
 13. The dosage form of claim 12, in which thethird portion comprises a chemical reaction product of the first andsecond materials.
 14. The dosage form of claim 12, in which the thirdportion is impermeable to one or more active ingredients contained inthe dosage form.
 15. The dosage form of claim 12, in which the thirdportion is impermeable to water.
 16. The dosage form of claim 12, inwhich the third portion acts as a barrier to the passage therethrough ofone or more active ingredients contained in the first or secondportions.
 17. The dosage form of claim 12, in which the third portionfunctions to control the passage of one or more active ingredientscontained in the first or second portions.
 18. The dosage form of claim12, in which the third portion comprises openings which allow thepassage of one or more active ingredients therethrough.
 19. The dosageform of claim 12, in which the third portion comprises a microelectronicdevice.
 20. The dosage form of claim 1, in which the first and secondportions have different colors.
 21. The dosage form of claim 1, in whichthe first and second portions have different opacities.
 22. The dosageform of claim 1, in which the first and second portions have differentsolubilities in acidic, alkaline or neutral aqueous media.
 23. Thedosage form of claim 1, in which the first and second portions havedifferent dissolution rates in acidic, alkaline or neutral aqueousmedia.
 24. The dosage form of claim 1, in which the first and secondportions have different disintegration times in acidic, alkaline orneutral aqueous media.
 25. The dosage form of claim 1, in which thefirst and second portions have different hydrophilicities.
 26. Thedosage form of claim 1, in which the first and second portions havedifferent topographies.
 27. The dosage form of claim 1, in which thefirst and second portions have different elasticities.
 28. The dosageform of claim 1, in which the first and second portions have differentplasticities.
 29. The dosage form of claim 1, in which the first andsecond portions have different tensile strengths.
 30. The dosage form ofclaim 1, in which the first and second portions have differentcrystallinities.
 31. The dosage form of claim 1, in which the first andsecond portions each comprise at least one active ingredient, andrelease active ingredient at different rates.
 32. The dosage form ofclaim 1, wherein the first portion is obtained by injection molding. 33.The dosage form of claim 1, wherein the second portion is a substrate,and the first portion is formed directly upon the first portion.
 34. Thedosage form of claim 1, in which the first portion comprises at leastone active ingredient.
 35. The dosage form of claim 1, in which thesecond portion comprises at least one active ingredient.
 36. The dosageform of claim 1, in which both the first and the second portionscomprise at least one active ingredient which may be the same ordifferent.
 37. The dosage form of claim 1, in which the first portionfurther comprises an insert.
 38. The dosage form of claim 1, in whichthe second portion further comprises an insert.
 39. The dosage form ofclaim 37, in which the insert is molded.
 40. The dosage form of claim 1,in which the first portion is contained within the second portion. 41.The dosage form of claim 1, in which at least one active ingredient iscapable of dissolution, and dissolution of the active ingredient meetsUSP specifications for immediate release tablets containing the activeingredient.
 42. The dosage form of claim 1, in which the second materialis a compressed material.
 43. The dosage form of claim 1, in whicheither the first portion, the second portion or both comprises amicroelectronic device.
 44. The dosage form of claim 1, in which a shellresides upon the outer surfaces of the first and second portions. 45.The dosage form of claim 1, wherein the surface of the first portion atthe interface has indentations and protrusions correspondingsubstantially inversely to indentations and protrusions on the surfaceof the second portion at the interface.
 46. The dosage form of claim 45,wherein the indentations and protrusions have a length, width, height ordepth greater than 10 microns.
 47. The dosage form of claim 1, whereinthe area of the interface surfaces is at least 50% of the area of amajor face of either the first or second portion.
 48. The dosage form ofclaim 1, wherein an entire face of the first portion is in substantialcontact with the second portion.
 49. The dosage from of claim 1, whereinan entire face of the second portion is in substantial contact with thefirst portion.
 50. The dosage form of claim 1 wherein one face or sideof the second portion comprises a cavity, and the first portion is incontact with the entire surface of the cavity.
 51. The dosage form ofclaim 1, wherein at least one exterior surface of the first portion isflush with at least one exterior surface of the second portion.
 52. Thedosage form of claim 38, in which the insert is molded.